Human papillomavirus infection is associated with the development of benign and malignant neoplasms of the skin, anogenital and ororespiratory tract, for which there is no known curative method of treatment. The following grant proposal outlines clinical and experimental studies involving the use of Ribavirin(TM) (1-beta-D-ribofuranosyl-1,2,4-triazole- 3-carboxamide), a nucleoside analogue, for the anti-viral treatment of HPV infected tissues. Based on early experimental success with Dutch belt rabbits infected with Cottontail rabbit papillomavirus (CRPV), which produces cutaneous warts, moderately high doses of intradermally injected ribavirin were found to be extremely effective at preventing the appearance of measurable warts in animals treated at the time of virus infection. In addition ribavirin reduced the rate of wart growth in animals with established warts. These effects were most pronounced when the tumor load was low. This indicated that ribavirin could also be an effective antiviral agent for human papillomavirus-induced disease. We have now completed an uncontrolled pilot clinical trial of intravenous/oral ribavirin treatment in four patients severely affected with longstanding laryngeal papillomatosis. The results have shown ribavirin to be an effective adjunct to laser extirpation of ororespiratory tract papillomas. All four patients responded with a partial or complete clinical remission of papillomatous growth, thereby reducing the need for frequent laser surgeries. Side effects of ribavirin treatment were minimal and readily reversible. This grant application proposes two major lines of investigation: First, we will perform controlled clinical trials to evaluate the efficacy of intravenous/oral ribavirin for the treatment of laryngeal papillomatosis. This trial will be conducted as a phase II double-blinded, controlled crossover and prospective clinical trial of two years duration on thirty-five patients exhibiting infantile, juvenile or adult laryngeal papillomatosis. Second, we will correlate the clinical response in these patients with several pathologic parameters including the HLA phenotype and the HPV type, as well as specific histologic features of these lesions. Based upon our pilot study, we believe that ribavirin will again be shown to be a useful adjunctive treatment for LP in this larger group under more controlled conditions.